Background/aim : Autism spectrum disorder (ASD) describes a range of neurodevelopmental disabilities that impair behavior and communication. Although it is relatively prevalent, the pathophysiology is still subject to speculation and debate. The aim of this study is to identify a possible association between interleukin-6, -8, -9, and -10 and tumor necrosis factor alpha (TNF-alpha) in autism among Jordanian children by comparing the plasma levels of these cytokines in autistic children with those of their unaffected siblings and unrelated healthy controls. Materials and methods : In this study, 80 Jordanian children under the age of 12 with diagnosed autism were selected. For comparison, 51 unaffected siblings and 86 unrelated healthy controls were also recruited. Venous blood was collected and interleukin levels in all three groups were investigated. Results : Interleukin-6 was found to be significantly higher in the plasma of both autistic children and their siblings compared with the unrelated healthy control group (P < 0.05). As for interleukin-8 and TNF-alpha, plasma levels were significantly higher exclusively in autistic children compared to their siblings and unaffected control subjects (P < 0.001, P < 0.001). There was no significant difference between plasma levels of the previously mentioned cytokines in the siblings and the unrelated control group. As for interleukin-9 and interleukin-10, no significant differences were found between all three groups (P = 0.15, P = 0.35). Conclusion : We found that interleukin-8 and TNF-alpha were exclusively elevated in autistic Jordanian children, while interleukin-6 was elevated in both autistic children and their siblings, potentially dismissing its significance. These results may lead to a better understanding of the disorder’s pathophysiology, early testing, and diagnosis.

AIM : Links between autism spectrum disorder (ASD) and autoimmune diseases, including Type 1 diabetes have been proposed. This study assessed the frequency of ASD in children with Type 1 diabetes in the T1D Exchange (T1DX) registry and the impact of ASD on characteristics of children with Type 1 diabetes. METHODS : Analysis included 10 032 participants aged < 18 years (median Type 1 diabetes duration 6.5 years, 48% female, 77% non-Hispanic White). Diagnosis of ASD was defined as autism, Asperger’s or pervasive developmental disorder. RESULTS : A diagnosis of ASD was recorded for 159 (1.58%) participants. Those with ASD were predominantly male (88% vs. 51% of those without ASD, P < 0.001) and slightly older (median 14 vs. 13 years, P = 0.022). Occurrence of diabetic ketoacidosis at Type 1 diabetes diagnosis was similar (35% vs. 41%, P = 0.161). Pump use was lower in those with ASD (51% vs. 63%, P = 0.005) but continuous glucose monitor use was similar (24% vs. 27%, P = 0.351). Median HbA1c was slightly lower in those with ASD [68 vs. 69 mmol/mol (8.4% vs. 8.5%), P = 0.006]. This difference was more pronounced after adjusting for confounders. CONCLUSIONS : The frequency of ASD in the T1DX registry was similar to that in the general population. These data show that despite deficits in communication, occurrence of diabetic ketoacidosis was similar in youth with and without ASD. Pump use was less frequent in those with ASD, possibly due to sensory issues, although CGM use did not differ. The lower HbA1c may be due to a more regimented routine with ASD. Because comorbidities such as ASD complicate care of patients with Type 1 diabetes, further research is needed to support these children. This article is protected by copyright. All rights reserved.

Despite efforts to improve employment outcomes for autistic individuals, internationally their employment rates remain low. There is a need to better understand the factors influencing successful employment for autistic adults in the labor market from the perspectives of multiple key stakeholders. This study represents the second in a series of papers conducted as part of an International Society for Autism Research policy brief aimed at improving employment outcomes for autistic individuals. A community consultation methodology using focus groups, forums, and interviews was applied with autistic individuals (n = 19), family members (n = 18), service providers (n = 21), employers (n = 11), researchers (n = 5), and advocacy group representatives (n = 5) in Australia, Sweden, and the United States, aiming to identify the factors perceived to determine gaining and maintaining employment for autistic individuals. Directed content analysis, guided by the International Classification of Functioning, Disability and Health (ICF), was conducted to investigate the key factors influencing employment outcomes for autistic individuals. Meaningful verbal concepts, or units of text with common themes, were also derived from the qualitative data and then linked and compared to the ICF Autism Spectrum Disorder (ASD) Core-sets. Across countries, activity and participation and environmental factor categories of the ICF were the most associated with employment outcomes. Results suggest that removal of environmental barriers and enhancing environmental facilitators may assist to remediate ASD-related difficulties in the workplace. Autism Res 2019, (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : This study sought to understand the perspectives of autistic individuals and key stakeholders on factors influencing if autistic adults get and keep jobs. Across Australia, Sweden, and the United States, focus groups and interviews were conducted to understand international perspectives on what helps and hinders getting and keeping a job for autistic individuals. The environment, including supports, relationships, attitudes, and services, were perceived to be the most important for workplace success. Intervention targeting barriers and facilitators in the workplace environment may support autistic adults to be successful in the labor market.

BACKGROUND : Compared to the general population, individuals with intellectual and developmental disabilities (IDD) more often experience bullying and its negative social and emotional impacts. Prior studies explored bullying of individuals with IDD primarily through investigations of the perspectives of others and the negative impacts of bullying. The current study examined how individuals with IDD describe their responses to experiences of bullying, with a focus on whether responses included component skills of self-determination. METHOD : Eighteen adults with IDD (50% female) aged 18-63 years were interviewed about their experiences with bullying. Interviews were analysed to determine responses to bullying and the degree to which their responses demonstrated self-determination. RESULTS : Data analysis revealed two primary themes, outside support and self-determination, with additional subthemes. CONCLUSIONS : Findings provide a more nuanced description of the ways in which individuals with IDD respond to bullying, including the demonstration of self-determination skills. Implications for research and practice are discussed.

Co-morbid mental health conditions such as anxiety and depression are extremely common in autistic adults. Vulnerability to negative life experiences such as victimisation and unemployment may be partially responsible for the development of these conditions. Here we measure the frequency of negative life experiences in autistic adults and explore how these are associated with current anxiety and depression symptoms and life satisfaction. We developed the Vulnerability Experiences Quotient (VEQ) through stakeholder consultation. The VEQ includes 60 items across 10 domains. Autistic adults with a clinical diagnosis and non-autistic controls completed the VEQ, screening measures for anxiety and depression, and a life-satisfaction scale in an online survey. Likelihood of experiencing each VEQ event was compared between groups, using binary logistic regression. Mediation analysis was used to test whether total VEQ score mediated the relationship between autism and (1) depression (2) anxiety and (3) life satisfaction. Autistic adults (N = 426) reported higher rates of the majority of events in the VEQ than non-autistic adults (N = 268). They also reported more anxiety and depression symptoms and lower life satisfaction. Group differences in anxiety, depression and life satisfaction were partially mediated by VEQ total score. This study highlights several important understudied areas of vulnerability for autistic adults, including domestic abuse, contact with social services (as parents) and financial exploitation and hardship. Improved support, advice and advocacy services are needed to reduce the vulnerability of autistic adults to negative life experiences, which may in turn improve mental health and life satisfaction in this population. Autism Res2019. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY : This study investigated whether autistic adults are more vulnerable to certain negative life experiences, and whether these experiences are related to anxiety, depression and life satisfaction. We found that autistic adults are more vulnerable to many different negative life events, including employment difficulties, financial hardship and domestic abuse. Negative life experiences partially explained the higher rates of anxiety and depression symptoms and lower life satisfaction in autistic adults compared to non-autistic adults. Improved support services are required to reduce the vulnerability of autistic adults. Reducing vulnerability may improve mental health and increase life satisfaction in this population.

AIMS : Bladder and bowel dysfunction (BBD) have been recognized in children affected by autism spectrum disorder (ASD), but no consistent information exist in adults with the condition. We evaluated the prevalence of BBD and the impact of psychiatric and behavioural profiles in adults affected by ASD. METHODS : Twenty-two adults and 13 children/teens with ASD and a matched group of typically developing subjects (TD) were prospectively studied. Patients and TD subjects underwent the evaluation of urinary incontinence (UI : diurnal, continuous or intermittent), nocturnal enuresis (NE), and bowel disturbances with the 3-day voiding and bowel diary. In addition, assessment of intellectual disability (ID) and psychiatric and adaptive behaviours with the Neuropsychiatric Inventory Scale (NPI) and the Vineland Adaptive Behaviour Scale 2nd Edition (Vineland-II), was performed. RESULTS : In adults, any type of incontinence was observed in 81.8% of cases, and NE and intermittent UI in 59.0% and 36.3% of patients, respectively. Faecal incontinence and constipation were detected 36.3% and in 68.1% of cases, respectively. ID was severe in 2 cases and profound in 18 ; NPI and Vineland-II items most affected were "Irritability/Lability," "Motor Activity," and "Agitation," and IQ-Socialization and IQ-Communication. Significant relationships were identified between intermittent UI and greater ID (P < .02) and high "anxiety" (P < .05), and between NE and high "euphoria/elevated mood" (P < .05). These results were similar to those observed in children/teens. CONCLUSIONS : Adults with ASD, and greater ID and mood disorders, present with a high prevalence of BBD. A shared pathogenetic mechanism could underlie the co-occurrence of ASD, mood disorders, and BBD.

BACKGROUND : As individuals with intellectual and developmental disabilities (IDD) grow older, siblings are likely to become caregivers for their brothers and sisters with IDD. Thus, it is important to identify the correlates of sibling caregiving to facilitate transitions to caregiving roles. METHOD : This study involved the secondary analysis of a national data set of 429 adult siblings of individuals with IDD. RESULTS : Current sibling caregiving was positively correlated with sibling relationship quality, sibling advocacy and future planning, maladaptive behaviours of individuals with IDD, and family size. Current sibling caregiving was negatively correlated with parent caregiving abilities and functional abilities of individuals with IDD. Further, among siblings who provided care, the level and nature of sibling caregiving were negatively correlated with parent caregiving abilities. CONCLUSIONS : The results identify the correlates of current caregiving among siblings of individuals with IDD. More research is needed to understand current sibling caregiving.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that has a strong genetic component. Disruptions of FOXP1, a transcription factor expressed in the developing cerebral cortex, were associated with ASD. FOXP1(R525X) is a de novo heterozygous mutation found in patients with autism and severe mental retardation. To explore the neuronal basis of FOXP1(R525X) in ASD, we created Foxp1(R521X), a mouse homolog of the human variant. Ectopic expression of Foxp1(R521X) led to cytoplasmic aggregates and activated macroautophagy in neuroblastoma N2a cells and the developing neuronal cells. Cortical neurons expressing Foxp1(R521X) exhibited delayed migration and altered dendritic morphology. As a control, mutant Y435X that was expressed diffusively in the cytoplasm did not induce autophagy and migration delay in the cortex. The embryonic cortical cells had a minimal activity of nonsense-mediated mRNA decay (NMD) as assayed by a splicing-dependent NMD reporter. We hypothesize that the developing neuronal cells use autophagy but not NMD as a safeguard mechanism against nonsense mutant aggregates, resulting in impairment of the cortical development. This study suggests a novel mechanism other than heterozygous loss of FOXP1 for the development of ASD and may advance our understanding of the complex relationships between gene mutation and the related psychiatric disorders.

The variability in the own-gender bias (OGB) in face-recognition is thought to be based on experience and the engagement of expert face processing mechanisms for own-gender faces. Experience is also associated with personality characteristics such as extraversion and Autism, yet the effects of these variables on the own-gender bias has not been explored. We ran a face recognition study exploring the relationships between own-gender experience, holistic processing (measured using the face-inversion effect, composite face effect, and the parts-and-wholes test), personality characteristics (extraversion and Autism Quotient) and the OGB. Findings did not support a mediational account where experience increases holistic processing and this increases the OGB. Rather, there was a direct relationship between extraversion and Autism Quotient and the OGB. We interpret this as personality characteristics having an effect on the motivation to process own-gender faces more deeply than opposite-gender faces.

The number of trials aimed at evaluating treatments for autism spectrum disorder has been increasing progressively. However, it is not clear which outcome measures should be used to assess their efficacy, especially for treatments which target core symptoms. The present review aimed to provide a comprehensive overview regarding the outcome measures used in clinical trials for people with autism spectrum disorder. We systematically searched the Web of Knowledge(SM) database between 1980 and 2016 to identify published controlled trials investigating the efficacy of interventions in autism spectrum disorder. We included 406 trials in the final database, from which a total of 327 outcome measures were identified. Only seven scales were used in more than 5% of the studies, among which only three measured core symptoms (Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale, and Social Responsiveness Scale). Of note, 69% of the tools were used in the literature only once. Our systematic review has shown that the evaluation of efficacy in intervention trials for autism spectrum disorder relies on heterogeneous and often non-specific tools for this condition. The fragmentation of tools may significantly hamper the comparisons between studies and thus the discovery of effective treatments for autism spectrum disorder. Greater consensus regarding the choice of these measures should be reached.

Age of first walking (AOW) is reported to be later in autism spectrum disorder (ASD) compared with typical development. However, the relationship between AOW and variations in ASD symptoms across different neurodevelopmental disorders is largely unknown. This study investigated AOW and its association with autism symptom severity in a large sample of children (N = 490, 23% females) clinically evaluated for suspected ASD, differentiated into ASD (n = 376) and non-ASD (n = 114) diagnoses. Children with ASD achieved independent walking significantly later than children with non-ASD diagnoses. AOW was significantly associated with ASD symptom severity, and females had a non-significant later AOW. The current findings suggest that in cases with delayed AOW, ASD should be considered as an actual differential diagnosis, perhaps particularly in girls.

Autism spectrum disorders (ASDs) are a group of diseases that affect social interaction, communication and behavior. Molecular mechanisms involved in the pathogenesis of ASDs are complex due to genetic heterogeneity. Recently, pathogenic variants of SCN2A have been strongly associated with ASDs. Here, we generated iPSCs from a patient with ASD and a heterozygous nonsense mutation in SCN2A, by reprogramming mesenchymal stromal cells with non-integrating vectors. The generated iPSC line expresses pluripotency markers, presents a normal karyotype and is able to differentiate into the three germ layers. This iPSC line is a useful tool for modeling ASD and drug screening studies.

Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. The Fmr1 knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult male Fmr1 KO mice produce fewer ultrasonic vocalizations (USVs) during mating, suggestive of abnormal social communication. Minocycline treatment for 2 months from birth alleviates a number of FXS phenotypes in mice, including USV call rate deficits. In the current study, we investigated if treatment initiated past the early developmental period would be effective, given that in many cases, individuals with FXS are treated during later developmental periods. Wildtype (WT) and Fmr1 KO mice were treated with minocycline between postnatal day (P) 30 and P58. Mating-related USVs were then recorded from these mice between P75 and P90 and analyzed for call rate, duration, bandwidth, and peak frequency. Untreated Fmr1 KO mice call at a significantly reduced rate compared to untreated WT mice. After minocycline treatment from 1-2 months of age, WT and Fmr1 KO mice exhibited similar call rates, due to an increase in calling in the latter group. Minocycline is thought to be effective in reducing FXS symptoms by lowering matrix-metalloproteinase-9 (MMP-9) levels. To determine whether abnormal MMP-9 levels underlie USV deficits, we characterized USVs in Fmr1 KO mice which were heterozygous for MMP-9 (MMP-9(+/-)/Fmr1 KO). The MMP-9(+/-)/Fmr1 KO mice were between P75 and P90 at the time of recording. MMP-9(+/-)/Fmr1 KO mice exhibited significantly increased USV call rates, at times even exceeding WT rates. Taken together, these results suggest that minocycline may reverse USV call rate deficits in Fmr1 KO mice through attenuation of MMP-9 levels. These data suggest targeting MMP-9, even in late development, may reduce FXS symptoms.

The shape bias, a preference for mapping new word labels onto the shape rather than the color or texture of referents, has been postulated as a word learning mechanism. Previous research has shown deficits in the shape bias in children with autism even though they acquire sizeable lexicons. While previous explanations have suggested the atypical use of color for label extension in individuals with autism, we hypothesize an atypical mapping of novel labels to novel objects, regardless of the physical properties of the objects. In Experiment 1, we demonstrate this phenomenon in some individuals with autism, but the novelty of objects only partially explains their lack of shape bias. In a second experiment, we present a computational model that provides a developmental account of the shape bias in typically developing children and in those with autism. This model is based on theories of neurological dysfunctions in autism, and it integrates theoretical and empirical findings in the literature of categorization, word learning, and the shape bias. The model replicates the pattern of results of our first experiment and shows how individuals with autism are more likely to categorize experimental objects together on the basis of their novelty. It also provides insights into possible mechanisms by which children with autism learn new words, and why their word referents may be idiosyncratic. Our model highlights a developmental approach to autism that emphasizes deficient representations of categories underlying an impaired shape bias. This article is protected by copyright. All rights reserved.

AIM : Although advanced parental age holds an increased risk for autism spectrum disorder (ASD), its role as a potential risk factor for an atypical white matter development underlying the pathophysiology of ASD has not yet been investigated. The current study was aimed to detect white matter disparities in ASD, and further investigate the relationship of paternal and maternal age at birth with such disparities. METHODS : Thirty-nine adult males with high-functioning ASD and 37 typically developing (TD) males were analyzed in the study. FMRIB Software Library and Tract-Based Spatial Statistics were utilized to process and analyze the diffusion tensor imaging data. RESULTS : Subjects with ASD exhibited significantly higher mean diffusivity (MD) and radial diffusivity (RD) in white matter fibers including the association (inferior fronto-occipital fasciculus, right inferior longitudinal fasciculi, superior longitudinal fasciculi, uncinate fasciculus, and cingulum), commissural (forceps minor), and projection tracts (anterior thalamic radiation, and right corticospinal tract) compared to TD subjects (Padjusted < .05). No differences were seen in either fractional anisotropy or axial diffusivity. Linear regression analyses assessing the relationship between parental ages and the white matter aberrations revealed a positive correlation between paternal age (PA), not maternal age (MA), and both MD and RD in the affected fibers (Padjusted < .05). Multiple regression performed, showed that only PA was a predictor of both MD and RD." CONCLUSION : Our findings suggest that PA contributes to the white matter disparities seen in individuals with ASD compared to TD. This article is protected by copyright. All rights reserved.

OBJECTIVE : To establish an improved mouse model of valproic acid (VPA)-induced autism that better mimics human autism. METHODS : We established mouse models of autism in female C57 mice by intraperitoneal injection of sodium valproate either at a single dose (600 mg/kg) on day 12.5 after conception (conventional group) or in two doses of 300 mg/kg each on days 10 and 12 after conception (modified group), and the control mice were injected with saline only on day 12.5. The responses of the mice to VPA injection, the uterus, mortality rate, and abortion rate were compared among the 3 groups. The morphology and development of the offspring mice were assessed, and their behavioral ontogeny was evaluated using 3- chambered social test, social test, juvenil play test, and open field test. RESULTS : The mortality and abortion rates were significantly lower in the modified model group than in the conventional group (P < 0.01). Compared with those in the control group, the offspring mice in both the conventional group and the modified group showed developmental disorders (P < 0.05). The mortality rate of the newborn mice was significantly lower in the modified group than in the conventional group with a rate of curvy tail of up to 100% (P < 0.001). The offspring mice in both the modified group and conventional group exhibited autism-like behavioral abnormalities, including social disorder and repetitive stereotyped behavior (P < 0.05). CONCLUSIONS : The mouse model of autism established using the modified method better mimics human autism with reduced mortality and abortion rates of the pregnant mice and also decreased mortality rate of the newborn mice.